Organs subject to various surgical procedures and/or organs for transplantation (grafts) often face a period of diminished or interrupted blood flow (e.g., during a surgical procedure, as a consequence of injury, or during removal and transit for transplants). Organ transplants, in particular, face a period of having to survive outside the donor and recipient. During that time, although grafts are preserved by cooling and other measures, they are short of blood supply (ischemia). Prolonged ischemia can be damaging because of lack of oxygen and nutrients. When the graft organ is attached to the blood circulation of the recipient, or when circulation is restored to an organ in a surgical procedure and/or as a consequence of repair to damage, the tissue is suddenly reperfused with blood (reperfusion). However, instead of restoring normal function, reperfusion can result in inflammation and additional damage to the organ, an event known as reperfusion injury. This type of reperfusion-related inflammation and cellular insult can further destroy an already damaged/ischemic graft. Depending on the severity of the initial ischemia, the tissue can subsequently be seriously or permanently damaged, subjecting the newly transplanted graft to an increased risk of graft dysfunction/failure and subsequent organ rejection from the recipient. The severe form of ischemia/reperfusion injury associated with solid organ transplantation is a life-threatening condition.
Ischemia and reperfusion injury (IRI) can occur during hepatic surgery with clamping of the vascular pedicle of the porta hepatis (Pringle Maneuver) and in liver transplantation (LT). Liver IRI has a profound clinical impact on graft function after LT when organs from marginal or extended criteria donors are used because its deleterious effects are augmented in these grafts (Merion et al. (2006) Ann. Surg., 244: 555-562; Cameron et al. (2006) Ann. Surg., 243: 748-753; Anderson et al. (2011) Liver Transpl., 17: 189-200). IRI causes up to 12% of early organ failure and 15% to 25% of long-term graft dysfunction (Hilmi et al. (2008) Liver Transpl., 14: 504-508). Post-reperfusion syndrome, with an incidence rate of up to 30%, causes acute cardiovascular collapse that may lead to death of the patients (Aggarwal et al. (1987) Transpl. Proc., 19: 54-55; Bukowicka et al. (2011) Ann. Transplant, 16: 26-30; Paugam-Burtz et al. (2009) Liver Transpl., 15: 522-529). Poor graft function after LT contributes to the need for retransplantation of the liver and results in an increase in resource utilization.
Hepatic IRI begins with an interruption of blood flow to the liver (ischemia) that leads to depletion of energy substrates and oxygen (Goto et al. (1992) Hepatology, 15: 432-437), acidosis, impaired adenosine triphosphate (ATP) regeneration (Karwinski et al. (1989) J. Surg. Res., 46: 99-103; Kamiike et al. (1985) Transplantation, 39: 50-55), and reduction of endogenous antioxidant glutathione (GSH) (Kurokawa et al. (1996) J. Surg. Res., 66: 1-5), and the reduced form of nicotine adenine dinucleotide (NADH), a key enzyme in the electron transport chain (Tomitsuka et al. (2010) Ann. N.Y. Acad. Sci., 1201: 44-49; Siegel et al. (2011) Acta. Physiol. (Oxf), 203: 225-234). Furthermore, ischemia also results in calcium influx across the plasma membrane and breakdown of the plasma membrane barrier (Kurita et al. (1993) J. Hepatol., 18: 196-204; Uchida et al. (1994) J. Hepatol., 20: 714-719). Paradoxically, the return of blood flow after a period of ischemia (reperfusion) results in induced oxidative stress and further hepatocyte injury through a complex cascade of events that include the infiltration of activated neutrophils in hepatic endothelial cells and systemic release of inflammatory mediators, reactive oxygen species (ROS) and proteases (Weiss (1989) N. Engl. J. Med., 320: 365-376). This state of cellular metabolic debt, in addition to other immunological and inflammatory mediators, result in the activation of the mitochondrial permeability transition (MPT), a key process in this lethal cell injury, leading to mitochondrial swelling, depolarization, uncoupling, plasma membrane rupture, and subsequent cell death (Weiss (1989) N. Engl. J. Med., 320: 365-376; Jaeschke (2000) J. Gastroenterol. Hepatol., 15: 718-724; Kim et al. (2003) Curr. Mol. Med., 3: 527-535; Nishimura (1998) Hepatology, 27: 1039-1049). The ability of the cell to recover from this type ischemic insult is dependent upon the energy state of the cell prior to organ reperfusion. While a brief period of warm ischemia (WI) may not cause significant alteration in the energy reserve of the mitochondria, prolonged WI results in a state of severe cellular metabolic deficit, an increased in toxic metabolites present in the host splanchnic venous blood, and an elevated portal reperfusion pressure that further predispose the compromised hepatocytes to reperfusion injury.